The objective of this proposal is to test the hypothesis that the pharmacological action of delta 1-tetrahydrocannabinol (delta a-THC) are at least in part expressed through alterations in cyclic nucleotide metabolism in the target cell. We have shown an antagonistic action of delta 1-THC on the enhancement of cyclic AMP levels by prostaglandin E1 (PGE1) in cultured WI-38 fibroblasts, and now propose to study possible interactions of delta 1-THC with all known components of the cyclic nucleotide system. We will characterize further the antagonistic effects of delta 1-THC in the fibroblast system, including comparisons of delta 1-THC action with the effects of a number of cannabinol analogs and derivatives. Possible changes in cyclic GMP levels will be monitored and we will determine the effects of the various cannabinols on the rate and extent of release of cyclic nucleotides into the incubation medium. Secondly, we will determine the effects of the cannabinols on various intracellular systems which may be regulated by changes in cyclic nucleotide levels. These include protein kinase activity, glycogen metabolism, collagen synthesis, prostaglandin synthesis and release, and cellular morphology. Third, we will attempt to determine the mechanism by which delta 1-THC alters cyclic AMP metabolism in WI-38 cells. These studies will include determinations of the effects of the cannabinols on adenyl cyclase and cyclic nucleotide phosphodiesterase activities in both intact cells and cell free systems. In addition, we will study the possible modulation of delta 1-THC action by various environmental factors such as serum, insulin, steroids, trypsin, and pH. On the basis of the above characterization and mechanistic studies, we will extend the investigations to other cell types, including SV40-transformed fibroblasts, rat cerebral cortical slices and isolated rat adipocytes, which show extreme difficulties in cyclic nucleotide regulation. Finally, time permitting, we will examine possible effects of psychotomimetic agents other than the cannabinols on cyclic nucleotide metabolism.